Novel prolinal derivatives

ABSTRACT

A novel prolinal derivative of general formula: ##STR1## wherein A represents alkylene group of from 1 to 4 carbon atom(s) or saturated hydrocarbon ring of from 3 to 7 carbon atoms, n represents a number 2, 3 or 4, D represents carbocyclic or heterocyclic ring unsubstituted or substituted by from one to three of halogen atom, alkyl or alkoxy group of from 1 to 4 carbon atom(s), nitro group or trifluromethyl group posses inhibitory activity on prolyl endopeptidase, and therefore are useful for treating and/or preventing agent for amnesia.

SUMMARY

This invention is related to novel compounds having an inhibitoryactivity on prolyl endopeptidase.

More particularly, this invention is related to

(1) Novel prolinal derivatives having an inhibitory activity on prolylendopeptidase, of the following general formula: ##STR2## wherein all ofthe symbols are the same meaning as defined hereafter.

(2) processes for the preparation of them, and

(3) anti-amnesia agents containing them as active ingredient.

BACKGROUND

Recent advances in neuroscience are making clear the natural shape ofneurotransmitters, substances deeply related to memory in brain. It issaid that some of these substances are neuropeptides containingprolines.

Recovery of the memory was reported by the dosage of a neuropeptidecontaining proline to an experimental amnesia rat (See Science 211, 601(1981)).

On the other hand, it is presumed that these neuropeptide - hormonsshall be metabolized by cerebral endogenous peptidases. Especially,prolyl endopeptidase (EC, 3. 4. 21. 26) might intimately take part insuch metabolism closely (See J. Biochem., 94, 1179 (1983)).

From these facts, studies were in progress based on the conclusion thatit should be possible to prevent or treat amnesia by inhibiting prolylendopeptidase and suppressing the metabolism of neutrotransmitter. (SeeProtein, Nucleic acid and Enzyme 25(6), 513(1980); Nippon Nougei KagakuKaishi 58(11), 1147(1984); J. Neurochem., 41, 69(1983); ibid 42,237(1984).)

For the purpose described above, several compounds were synthesized. Forexample, it is clear thatN-benzyloxycarbonyl-glycyl-L-prolyl-chloromethane,N-benzyloxycarbonyl-L-propyl-prolinal strongly inhibits prolylendopeptidase (See J. Neurochem., 41, 69 (1983)). More recently, it isdisclosed that the compounds shown below are effective for the abovepurpose.

(i) Prolinal derivatives of the general formula: ##STR3## wherein Arepresents a protecting group of amino acid group in the field of aminoacid chemical, and X represents a residual group of amino acid. SeeJapanese Patent Kokai No. 60-188317, i.e., European Patent PublicationNo. 154353.

(ii) N-acylpyrrolidine derivatives of the general formula: ##STR4##wherein n represents a number of 1˜4, and R represents lower alkyl estergroup, --CH₂ OH group or aldehyde group.

See Japanese Patent Kokai No. 61-37764; a compound wherein n is 5 isalso disclosed by correction, i.e., European Patent Publication No.172458.

(iii) Compounds of the general formula: ##STR5## wherein A representsmethyl group or benzyloxy group, R represents isopropyl group orisobutyl group on the condition that plural R's have the same meaning inone formula. And n represents 2 or 3.

See Japanese Patent Kokai No. 61-183297.

Most recently, five applications related to anti-amnesia agents havingprolinal skeltons were published, i.e.:

(iv) Compounds of the general formula: ##STR6## wherein R represents agroup of ##STR7##

See Japanese Patent Kokai No. 61-238775, i.e., European PatentPublication No. 201741.

(v) N-acylpyrrolidine derivatives of the general formula: ##STR8##wherein R³ represents lower alkyloxycarbonyl group, hydroxymethyl groupor formyl group, R¹ represents a hydrogen atom or lower alkyl group, R²represents phenyl group or a group of the following general formula:##STR9## wherein R⁴ represents a hydrogen atom, a halogen atom or loweralkoxy group, R⁵ represents a hydrogen atom or lower alkyl group, nrepresents 1 or 1, A represents an oxygen atom, methylene group,hydroxymethylene group, phenylmethylene group or carbonyl group. or R¹and R² represent, together with, benzylidene group unsubstituted orsubstituted by aromatic ring(s).

See Japanese Patent Kokai No. 61-238776, i.e., European PatentPublication No. 201742.

(vi) Compounds of the general formula: ##STR10## wherein n represents anumber of 0˜2, R¹ represents a straight-chained organic group of from 5to 25 carbon atoms which is saturated or unsaturated, wherein anunsaturated carbon chain may contain a plural number of double bonds, R²represents a group of ##STR11## and R³ represents lower alkyl estergroup, --CH₂ OH group or aldehyde group. See Japanese Patent Kokai No.61-238799, i.e., European Patent Publication No. 201743.

(vii) Compounds of the general formula: ##STR12## wherein n is aninteger of more than one, R₁ is a saturated or unsaturatedstraight-chained hydrocarbon group of from 5 to 25 carbon atoms, whereinsaid unsaturated carbon chain may contain a plural number of doublebonds, R³ represents lower alkyl ester group of the formula: --COOR⁴(wherein R⁴ represents lower alkyl group, hydroxymethyl group or formylgroup, R² represents methyl group, phenyl group, hydroxyphenyl group,indolyl group, imidazolyl group, carboxyl group, formyl group, aminogroup, hydroxy group, hydroxyalkyl group, thiol group, methylothio groupor guanidino group etc., and each of above groups may be substituted andR⁵ represents a hydrogen atom or a single bond between a carbon atom andnitrogen atom together with R² when n is 3.

See Japanese Patent Kokai No. 62-84058, i.e. European Patent PublicationNo. 201743.

(viii) Dipeptide derivatives of the general formula: ##STR13## wherein mrepresents an integer of 1˜8, n represents an integer of 1˜6, R¹represents a hydrogen atom, R² represents a hydrogen atom, a branchedalkyl group of from 3 to 5 carbon atoms, phenyl group, hydroxyphenylgroup, indolyl group, imidazolyl group or methylthio group, or a singlebond between a carbon atom and a nitrogen atom together with R¹ and R³represents lower alkyl ester group, hydroxymethy group or formyl group.

See Japanese Patent Kokai No. 62-148467, i.e., European PatentPublication No. 201741.

The present inventors have also filed an application related to prolinalderivatives having an anti amnesia activity, in advance of the presentapplication, i.e.

(ix) Prolinal derivatives of the general formula: ##STR14## wherein Arepresents alkylene or alkenylene group of from 1 to 8 carbon atom(s) ora saturated hydrocarbon ring of from 3 to 7 carbon atoms, R represents ahydrogen atom, phenyl group, benzyl group, alkyl group of from 1 to 8carbon atoms(s) or cycloalkyl group of from 3 to 7 carbon atoms, Brepresents alkylene group of from 1 to 8 atoms(s) unsubstituted orsubstituted by phenyl group or benzyl group, or a single bond, Drepresents carbocyclic or heterocyclic ring unsubstituted or substitutedby from one to three of halogen atom, alkyl or alkoxy group of from 1 to4 carbon atom(s), nitro group or trifluoromethyl group.

See Japanese patent Kokai No. 62-290631, i.e., European PatentApplication No. 87116613.8.

COMPARISON WITH THE PRIOR ART

The compounds of the present invention of the general formula (I) have aprolinal (pyrrolidine-2-al) skeleton in their structure and have aninhibitory activity on prolyl endopeptidase, being somewhat the same asthe compounds of the general formula (A)˜(J) and the compounds in theliterature [J. Neurochem., 41, 69 (1983].

But the compounds of the present invention are novel compounds whichhave a different structure from the compounds with the general formula(A)˜(J).

That is, the modification that the oxo group is introduced in thealkylene chain between a benzene ring and a prolinal has been known(described in (v) prior art: see Japanese Patent Kokai No. 61-238776,i.e., European Patent Publication No. 201743, and, in the specification,the oxo group combines directly to a benzene ring.

The compounds of the present invention also have introduced a longeralkylene chain between the benzene ring and the oxo group of generalformula (E), described in Prior Art, and we found that these compoundshave an inhibitory activity on prolyl endopeptidase.

Further, in certain compounds, we tried the modification describedhereinafter: to change part of A of the general formula (I) to asaturated hydrocarbon ring, to introduce substituent groups into 1benzene ring or to replace a benzene ring by a naphthalene ring.

Then we found all these modified compounds have an inhibitory activityon prolyl endopeptidase.

And we, the present inventors, confirmed in the previous application(compounds represented by the general formula (J)) that compoundswherein a benzene ring was replaced by other aromatic rings (includingheterocyclic rings and saturated rings, e.g., naphthalene, fluorene,furan rings) also maintained the inhibitory activity on prolylendopeptidase with several modification in D.

Among the compounds of the present invention which are modifiedcompounds of the general formula (J) in the parts other than D, it isnot difficult to forecast that the compounds wherein D was replaced bythe other rings should have maintained the activity, if the compoundswherein D is benzene ring have enough activity.

DISCLOSURE OF THE INVENTION

The present invention is related to

(1) A novel prolinal derivative of the general formula: ##STR15##wherein A represents alkylene group of from 1 to 4 carbon atom(s) orsaturated hydrocarbon ring of from 3 to 7 carbon atoms, n represents anumber of 2, 3 or 4, D represents carbocyclic or heterocyclic ringunsubstituted or substituted by from one to three of halogen atom, alkylor alkoxy group of from 1 to 4 carbon atom(s), nitro group ortrifluoromethyl group.

(2) Processes for the preparation of them; and

(3) Anti-amnesia agents containing them as an active ingredient.

In the general formula (I), "alkylene group of from 1 to 4 carbonatom(s)" represented by A means methylene, ethylene, trimethylene andtetramethylene groups and isomeric groups thereof.

In the general formula (I), "saturated hydrocarbon ring of from 3 to 7carbon atoms" represented by A means cyclopropane, cyclobutane,cyclopentane, cyclohexane and cycloheptane rings.

In the general formula (I), halogen atoms in D means fluorine, chlorine,bromine, iodine atoms, and alkyl group of from 1 to 4 carbon atom(s)means methyl, ethyl, propyl and butyl groups and isomeric groupsthereof, and alkoxy group of from 1 to 4 carbon atom(s) means methoxy,ethoxy, propoxy and butoxy groups and isomeric groups thereof.

In the general formula (I), "carbocyclic ring" represented by D meansmono-, bi- or tri-cyclic aromatic carbocyclic ring(s) containing notmore than 15 carbon atoms which may be partially or fully saturated.

Examples of the rings mentioned above are benzene, naphthalene, indene,azulene, fluorene, phenanthrene, anthracene, acenaphthalene, biphenylenerings and partially or fully saturated rings thereof.

In the general formula (I), "heterocyclic ring" represented by D meansmono-, bi- or tri-aromatic heterocyclic ring(s) containing not more than15 carbon and hetero atoms which may be partially or fully saturated. Inthe above heterocyclic rings, rings containing one or two hetero atom(s)are preferred.

Examples of the rings mentioned above are furan, thiophene, pyrrole,oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, furazan,pyran, pyridine, pyridazine, pyrimidine, pyrazine, indole, isoindole,benzofuran, benzothiophene, indolizine, chromene, quinoline,isoquinoline, quinolizine, purine, indazole, quinazoline, cinnoline,quinoxaline, phthalazine, pteridine, carbazole, acridine,phenanthridine, xanthene, phenazine, phenothiazine rings and partiallyor fully saturated rings thereof.

In the general formula (I), preferred rings represented by D especiallyare benzene and naphthalene rings and partially saturated rings thereof.

In the above rings, substituted benzene rings are preferred assubstituted rings with substituent(s).

Throughout the specification including the claims, stereo isomersgenerated by stereo configuration(s) (asymmetric carbon, etc.) andstructural isomers generated by branding of carbon chain, etc. areincluded in the present invention.

For example, it may be easily understood that alkylene and alkenylenegroups include straight-chained and also branched-chained ones, to theskilled in the art.

Rings represented by A or rings in D may be attached to the adjoinedgroup at any position.

The compounds of the present invention of the general formula (I) can beseparated into two groups of compounds represented by the generalformula: ##STR16## wherein ##STR17## represents saturated hydrocarbonring of from 3 to 7 carbon atoms, Alk represented alkylene group of from1 to 4 carbon atoms and the other symbols are the same meaning asdefined hereinbefore.

PROCESS FOR THE PREPARATION

According to the present invention, the compounds of the presentinvention of the general formula (I) may be prepared by oxidizingprolinol derivatives of the general formula: ##STR18## wherein all ofthe symbols are the same meaning as defined hereinbefore under mildconditions.

Oxidation under mild conditions is known and may be carried out, forexample, using an oxidation agent (sulfur trioxide - pyridine complex,chromium trioxide - pyridine complex, t-butyl chloroformate, oxalylchloride etc.), with or without a tertiary amine (triethylamine,pyridine etc.), in an inert organic solvent (DMSO, methylene chloride,chloroform, benzene etc.), at a temperature of from 0° C. to 50° C.

PROCESS FOR THE INTERMEDIATES

Prolinol derivatives represented by the general formula (II) or (III)may be prepared according to a series of reactions in scheme [A] shownhereinafter.

In the scheme [A], each symbol has the same means as definedhereinafter, or has the same meaning as defined hereinbefore.

B--alkenyl or alkynyl group of from 2 to 4 carbon atoms.

m--1, 2, 3 or 4.

Reaction A is the reaction of forming an amide-bond. ##STR19##

All reactions, described in the scheme [A], may be carried out by aknown method, and the starting materials and reagents used in eachreaction are all known per se or may be prepared by a known method.

Throughout the specification, in each reaction, products may be purifiedby conventional methods, for example, distillation at atmospheric orreduced pressure, high performance liquid chromatography, thin layerchromatography using silica gel or magnesium silicate or washing orrecrystallization. Purification may be carried out after each reactionsor a series of reactions.

PHARMACOLOGICAL ACTIVITIES

The compounds of the present invention of the general formula (I)possess an inhibitory activity on prolyl endopeptidase as describedbefore. For example, in a standard laboratory test, results in thefollowings are given.

Prolyl endopeptidase inhibitory activity in vitro

The compounds of the present invention showed activities as in thefollowing Table I, with the test system described hereafter.

                  TABLE I                                                         ______________________________________                                                       Concentration for                                              Example No. of 50% inhibition                                                 the compounds  IC.sub.50 (mN)                                                 ______________________________________                                        1.sup.  .sup.  27                                                             1 (a)          120                                                            1 (d)          150                                                            1 (e)          50                                                             1 (f)          62                                                             1 (g)          84                                                             1 (h)          29                                                             1 (i)          11                                                             1 (j)          32                                                             1 (k)          18                                                             1 (l)          39                                                             1 (m)          15                                                             1 (b)          14                                                             1 (c)          24                                                             ______________________________________                                    

Inhibitory activity of prolyl endopeptidase in vitro was measured by thefollowing test system.

A mixed solution of 20 mM tris-HCl buffer (pH 7.5; 935 μl; containing 10mM EDTA and 10 mM mercaptoethanol), a solution of a compound of thepresent invention in DMSO (10 μl) and a solution of prolyl endopeptidasewhich was purified from bovine brain (0.13 unit; prepared by the methoddescribed in J. Biochem., 94, 1179 (1983)) in tris-HCl buffer (15 μl)was preincubated for 15 mins at 37° C.

To the solution, 5 mM ofN-benzyloxycarbonyl-glycyl-prolyl-p-nitroanilide (40 μl) in a mixture of40% dioxane-60% water was added. The solution was incubated for 1 min atthe same temperature.

Optical absorption (a₁) at 405 nm of the solution, and opticalabsorption (a₂) at 405 nm of the solution after 30 mins' furtherincubation at 37° C. were measured.

Optical absorptions (b₁ and b₂) of the solutions using DMSO instead ofthe solution of the compound of the present invention were alsomeasured.

Inhibitory ratio was calculated by the following expression and IC₅₀(required concentration for 50% inhibition) was obtained (See Protein,Nucleic acid and Enzyme 25(6), 513, 1980.). ##EQU1##

TOXICITY

On the other hand, it was confirmed that the toxicity of the compoundsof the present invention was very low. Therefore, the compounds of thepresent invention may be considered to be sufficiently safe and suitablefor pharmaceutical use.

APPLICATION FOR PHARMACEUTICALS

To inhibit prolyl endopeptidase is to suppress the metabolism ofneurotransmitters, substances taking part in memory in the brain (eachof them is a peptide) as described hereinbefore, and therefore such canbe useful for prevention and/or treatment of amnesia, in animalsincluding human beings, especially human beings.

The compounds of the present invention possess an inhibitory activity onprolyl endopeptidase in vitro, so they are expected to be useful forprevention and/or treatment of amnesia.

For the purpose above described, the compounds of the present inventionmay normally by administered systemically or partially, usually by oralor parenteral administration.

The doses to be administered are determined depending upon age, bodyweight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment, etc. In the humanadult, the doses per person per dose are generally between 1 mg and 500mg, by oral administration, up to several times per day, and between 1mg and 100 mg, by parenteral administration (preferably, intravenousadministration) up to several times per day.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

At the administration, the compounds of the present invention may beformed into solid compositions, liquid compositions or othercompositions for oral administration, injection compositions, externalcomposition, suppositories, etc., for parenteral administration.

Solid compositions for oral administration, include compressed tablets,pills, dispersible powders, capsules, and granules. In suchcompositions, one or more of the active compound(s) is or are admixedwith at least one inert diluent (lactose, mannitol, glucose,hydroxypropylcellulose, microcrystalline cellulose, starch,polyvinylpyrrolidone, magnesium metasilicate aluminate etc.). Thecompositions may also comprise, as is normal practice, additionalsubstances other than inert diluents: e.g. lubricating agents (magnesiumstearate, etc.), disintegrating agents (cellulose calcium gluconate,etc.), assisting agents for dissolving (glutamic acid, aspertic acid,etc.) and stabilizing agents (lactose, etc.).

The tablets or pills may, if desired, be coated with a film of gastricor enteric material (sugar, gelatin, hydroxypropylcellulose orhydroxypropylmethyl cellulose phthalate, etc.).

Capsules include soft ones and hard ones.

Liquid compositions for oral administration includepharmaceutically-acceptable solutions, emulsions, suspensions, syrupsand elixirs.

In such compositions, one or more of the active compound(s) is or areused in inert diluent(s) commonly used in the art (purified water,ethanol, etc.).

Besides inert diluents, such compositions may also comprise adjuvants(wetting agents, suspending agents, etc.), sweetening agents, flavouringagents, perfuming agents and preserving agents.

Other compositions for oral administration include spray compositionswhich may be prepared by known methods and which comprise one or more ofthe active compound(s).

Spray compositions may comprise additional substances other than inertdiluents: e.g., stabilizing agents (sodium sulfite, etc.) isotonicbuffer (sodium chloride, sodium citrate, citric acid, etc.).

For preparation of such spray compositions, for example, the methoddescribed in the U.S. Pat. Nos. 2,868,691 or 3,095,355 may be used.

Injections for parenteral administration include sterile aqueous ornon-aqueous solutions, suspensions and emulsions. In such compositions,one or more active compound(s) is or are admixed with at least one inertaqueous diluent(s) (distilled water for injection, physiological saltsolution, etc.) or inert non-aqueous diluent(s) (propylene glycol,polyethylene glycol, olive oil, ethanol, POLYSOLBATE 80 (registeredtrade mark), etc.).

Injections may comprise other than inert diluents: e.g., preservingagents, wetting agents, emulsifying agents, dispersing agents,stabilizing agents (lactose, etc.) and assisting agents such asassisting agents for dissolving (glutamic acid, aspertic acid, etc.).

They may be sterilized, for example, by filtration through abacteria-retaining filter, by incorporation of sterilizing agents in thecompositions or by ;irradiation. They also be manufactured in the formof sterile solid compositions, for example, by freeze-drying, and whichcan be dissolved in sterile water or some other sterile diluents forinjection immediately before used.

Other compositions for parenteral administration include liquids forexternal use, and endermic liniments (ointment, etc.), suppositories andpessaries which comprise one or more of the active compound(s) and maybe prepared by known methods.

REFERENCE EXAMPLES AND EXAMPLES

The following reference examples and examples illustrate the presentinvention, but do not limit the present invention.

The solvents in the parentheses show the developing or eluting solventsand the ratios of the solvents used are by volume in chromatographicseparations.

Unless otherwise specified, "IR" were measured by a liquid film method,and "NMR" were measured using CDCl₃.

REFERENCE EXAMPLE 1 Synthesis of 7-phenyl-4-oxoheptanoic acid ##STR20##

Jones' reagents (3.4 ml; 2.6N) was added to acetone solution (6 ml) of7-phenylheptane-1,4-diol (630 mg), stirred for 1 hr.

The reaction mixture was diluted with ethylether, washed with water andsaturated aqueous solution of sodium chloride, successively, dried andevaporated to give the title compound (580 mg, partly, containingcorresponded lactone) having the following physical data:

TLC: Rf 0.14 and 0.43 (hexane:EtOAc=1:1)

REFERENCE EXAMPLE 2 Synthesis of N-(7-phenyl-4-oxoheptanoyl)-L-prolinal##STR21##

In an atmosphere of argon, diisopropylcarbodiimide (0.5 ml) was added tothe solution of methylene chloride (6 ml) of carbonic acid prepared inreference example 1 and the solution was stirred for 30 minutes.

L-prolinal (0.31 ml) was added thereto, and the reaction mixture wasstirred for 1 hr and left as it was for 18 hr at -5° C.

The reaction mixture was evaporated, and the residue was purified bycolumn chromatography on silica gel (hexane - EtOAc) to give the titlecompound (219 mg) having the following physical data:

TLC: Rf 0.20 (EtOAc);

NMR: δ 71-7.35 (5H,m), 4.05-4.25 (1H,m), 3.40-3.75 (4H,m), 2.40-2.80(8H,m), 1.8-2.2 (6H,m).

REFERENCE EXAMPLE 3 Synthesis of2-[3-(2-nitrophenyl)propyl]tetrahydrofuran-5-one ##STR22##

2-(3-phenylpropyl)tetrahydrofuran-5-one (230 mg) was dissolved inanhydrous acetic acid (1 ml), cooled with ice.

Concentrated nitric acid was added dropwise to the mixture.

20 mins later, the reaction mixture was stirred for 30 mins at roomtemperature.

Ethyl acetate was added to the reaction mixture and an oily layer waswashed with successive saturated aqueous solution of sodium bicarbonateand saturated aqueous solution of sodium chloride, and dried.

The residue was purified by column chromatography on silica gel(EtOAc:hexane=1:1) to give the title compound (255 mg) having thefollowing physical data:

TLC: Rf 0.21 or 0.24 (EtOAc:hexane=1:1).

REFERENCE EXAMPLE 4 Synthesis ofN-[4-hydroxy-7-(2-nitrophenyl)heptanoyl]-L-prolinal ##STR23##

L-prolinal (163 μl) was added to the solution of THF (5 ml) of lactone(prepared in reference example 3) and cooled with ice.

Sodium hydride was added to the reaction solution and the same stirredfor 30 mins at the same temperature.

The reaction solution was controlled to acidic with 1N hydro chloride,and ethyl acetate was added to the solution.

The oily layer was dried and evaporated to give the title compoundhaving the following physical data:

TLC: Rf 0.14 (EtOAc:CH₃ OH=95:5).

EXAMPLE 1 Synthesis of N-(7-phenyl-4-oxoheptanoyl)-L-prolinal ##STR24##

Triethylamine (0.32 ml) was added to the solution of dried-DMSO (1 ml)of prolinol (105 mg; prepared in reference example 2).

A solution of DMSO (1 ml) of sulfur trioxide-pyridine complex (185 mg)was added to the reaction solution and the same stirred for 20 mins atroom temperature.

The reaction solution was poured into ice water.

The mixture was stirred, and then ethyl acetate was added to themixture.

The oily layer was washed with successive, 1N hydrochloride andsaturated aqueous solution of sodium chloride and dried.

Then the reaction mixture was evaporated.

The residue was purified by column chromatography on silica gel(EtOAc:hexane=8:2) to give the title compound (69.4 mg) having thefollow physical data:

TLC: Rf 0.31 (EtOAc:Hexane-8:2);

IR: ν 2900, 1705, 1700, 1630, 1420, 735, 680 cm⁻¹.

EXAMPLE 1(a)˜1(m)

By the same procedure as described in reference example 1, 2 and example1, the compounds having the data described in the following Table IIwere prepared.

The compound of example 1(j) was prepared by using the compound ofreference example 4 as starting material. ##STR25##

                                      TABLE II                                    __________________________________________________________________________     No.pleam-Ex-                                                                                             Name             TLC      IR                      __________________________________________________________________________                                                         (cm.sup.-1)              1 (a)                                                                             ##STR26##              N-(6-phenyl-4-oxohexanoyl) L-prolinal                                                          Rf 0.40 (EtOAc)                                                                        ν 1725, 1710,                                                              1625,  1435, 1395        1 (b)                                                                             ##STR27##              N-[trans-2-(3-phenylpropanoyl) cyclopentanecarb                               onyl]-L-prolinal Rf 0.27 (hexane:EtOAc =                                                                ν 1715, 1690,                                                              1620,  1410, 730,                                                             690                      1 (c)                                                                             ##STR28##              N-[trans-2-(3-phenylpropanoyl) cyclohexanecarbo                               nyl]-L-prolinal  Rf 0.52 (hexane:EtOAc =                                                                ν 1715, 1690,                                                              1610,  1410, 730,                                                             685                      1 (d)                                                                             ##STR29##              N-(2RS-isopropyl-3-oxo-7-phenyl heptanoyl)-L-pr                               olinal           Rf 0.43 (hexane:EtOAc =                                                                ν 2950˜2850,                                                          1715,  1620, 1400,                                                           730,  690                1 (e)                                                                             ##STR30##              N-[6-(3-chlorophenyl)-4- oxohexanoyl]-L-prolina                               l                Rf 0.67 (EtOAc)                                                                        ν 2920, 1720,                                                              1705,  1630, 1430        1 (f)                                                                             ##STR31##              N-(4-oxo-8-phenyloctanoyl)- L-prolinal                                                         Rf 0.27 (hexane:EtOAc =                                                                ν 2800, 1710,                                                              1630,  1420, 1360,                                                            740,  690                1 (g)                                                                             ##STR32##              N-[6-(4-methoxyphenyl)-4- oxohexanoyl]-L-prolin                               al               Rf 0.25 (hexane:EtOAc =                                                                ν 3400, 1710,                                                              1620,  1500, 1420,                                                            1235,  1170, 1020        1 (h)                                                                             ##STR33##              N-[6-(4-chlorophenyl)-4- oxohexanoyl]-L-prolina                               l                Rf 0.30 (EtOAc)                                                                        ν 2900, 1710,                                                              1620,  1480, 1420,                                                            1080,   1000, 800        1 (i)                                                                             ##STR34##              N-[6-(4-methylphenyl)-4- oxohexanoyl]-L-prolina                               l                Rf 0.32 (hexane:EtOAc =                                                                ν 1700, 1620,                                                              1420,  795               1 (j)                                                                             ##STR35##              N-[7-(2-nitrophenyl)-4- oxoheptanoyl]-L-prolina                               l                Rf 0.15 (EtOAc:MeOH 97:3)                                                              ν 1720, 1705,                                                              1630,  1510, 1430,                                                            1420                     1 (k)                                                                             ##STR36##              N-[6-(1-naphthyl)-4- oxohexanoyl]-L-prolinal                                                   Rf 0.31 (EtOAc)                                                                        ν 2830, 1710,                                                              1630,  1425, 790,                                                             770  745                 1 (l)                                                                             ##STR37##              N-[6-(2-naphthyl)-4- oxohexanoyl]-L-prolinal                                                   Rf 0.31 (AcOEt)                                                                        ν 1710, 1630,                                                              1420,  810, 740          1 (m)                                                                              ##STR38##             N-[4-oxo-6-(p-trifluoro- methylphenyl)hexanoyl]                               -L-prolinal      Rf 0.33 (hexane:AcOEt =                                                                ν 1710,                                                                    1630˜1610,                                                              1430, 1320,                                                                   1150,mx,1   1110,                                                             1060, 1010,              __________________________________________________________________________                                                         820                  

FORMULATION EXAMPLE

The following components were admixed by a conventional method andpunched out to obtain 100 tablets each containing 50 mg of activeingredient.

    ______________________________________                                        N-(7-phenyl-4-oxoheptanoyl)-L-prolinal                                                                  5     g                                             Cellulose calcium gluconate                                                                             0.2   g                                             (disintegrating agent)                                                        Magnesium stearate        0.1   g                                             (lubricating agent)                                                           Microcrystaline cellulose 4.7   g                                             ______________________________________                                    

What is claimed is:
 1. A novel prolinal derivative of general formula:##STR39## where A represents alkylene group of from 1 to 4 carbonatom(s) or saturated hydrocarbon ring of from 3 to 7 carbon atoms, nrepresents a number 2, 3 or 4, D represents mono-, bi- ortri-carbocyclic ring(s) containing not more than 15 carbon atoms whichmay be partially or fully saturated or aromatic, wherein the saidring(s) represented by D is unsubstituted or substituted by from one tothree of halogen atom, alkyl or alkoxy group of from 1 to 4 carbonatom(s), nitro group or trifluoromethyl group.
 2. A compound accordingto claim 1, D represents phenyl or naphthyl unsubstituted or substitutedby from one to three of halogen atom, alkyl or alkoxy group of from 1 to4 carbon atom(s) or nitro group.
 3. A compound according to claim 1,which is a compound of the general formula: ##STR40## wherein ##STR41##represents saturated hydrocarbon ring of from 3 to 7 carbon atoms andthe other symbols have the same meaning as defined in claim
 1. 4. Acompound according to claim 1 or 3, whichis:N-(trans-2-(3-phenylpropanoyl)cyclopentanecabonyl)-L-prolinal orN-(trans-2-(3-phenylpropanoyl)cyclohexanecabonyl)-L-prolinal.
 5. Acompound according to claim 1, which is a compound of the generalformula: ##STR42## (wherein AlK represents alkylene group of from 1 to 4carbon atom(s), the other symbols are the same meaning as defined inclaim 1).
 6. A compound according to claim 5 wherein D is unsubstitutednaphthyl group.
 7. A compound according to claim 1 or 6, whichis:N-(6-(1-naphthyl)-4-oxohexanoyl)-L-prolinal orN-(6-(2-naphthyl)-4-oxohexanoyl)-L-prolinal.
 8. A compound according toclaim 5 wherein D is unsubstituted phenyl group.
 9. A compound accordingto claim 1 or 8, which is:N-(6-phenyl-4-oxohexanoyl)-L-prolinal,N-(7-phenyl-4-oxoheptanoyl)-L-prolinal,N-(8-phenyl-4-oxooctanoyl)-L-prolinal orN-(2RS-isopropyl-3-oxo-7-phenylheptancy)-L-prolinal.
 10. A compoundaccording to claim 5 wherein D is unsubstituted phenyl group.
 11. Apharmaceutical composition for treating amnesia which comprises, as anactive ingredient, an effective amount of prolinal derivative of thegeneral formula (I) depicted in claim 1 and pharmaceutical acceptablecarrier and/or coating.
 12. The method for treating amnesia whichcomprises administering a therapeutically effective amount of prolinalderivative of the general formula (I) depicted in claim
 1. 13. Acompound according to claim 1 or 10, whichis:N-(6-(4-methylphenyl)-4-oxohexanoyl)-L-prolinal,N-(6-(4-methoxyphenyl)-4-oxohexanoyl)-L-prolinal,N-(6-(4-chlorophenyl)-4-oxohexanoyl)-L-prolinal,N-(6-(3-chlorophenyl)-4-oxohexanoyl)-L-prolinal,N-(7-(2-nitrophenyl)-4-oxoheptanoyl)-L-prolinal orN-(4-oxo-6-(p-trifluoromethylphenyl)hexanoyl)-L-prolinal.N-(7-(2-nitrophenyl)-4-oxoheptanoyl)-L-prolinal orN-(4-oxo-6-(p-trifluoromethylphenyl)hexanoyl)-L-prolinal.